Synthesis and crystallographic analysis of meso-2,3-difluoro-1,4-butanediol and meso-1,4-dibenzyloxy-2,3-difluorobutane

Summary A large-scale synthesis of meso-2,3-difluoro-1,4-butanediol in 5 steps from (Z)-but-2-enediol is described. Crystallographic analysis of the diol and the corresponding benzyl ether reveals an anti conformation of the vicinal difluoride moiety. Monosilylation of the diol is high-yielding but all attempts to achieve chain extension through addition of alkyl Grignard and acetylide nucleophiles failed.


Introduction
Selective fluorination of bioactive compounds is a widely employed strategy for the modification of their properties [1]. Fluorine atoms can be introduced to modulate the pK a of adjacent acidic and basic functional groups as well as the lipophilicity, chemical and metabolic stability of the compound. Recent exciting reports describe weak but stabilising interactions between a C-F moiety and protein residues, which is certain to have implications in drug design [2,3]. Further important applications include molecular imaging using 18 F [4], and modification of high-performance materials [5].
In recent years, the vicinal difluoride motif has received increasing attention due to the conformational properties instilled by the 'gauche effect' [6], which results in the vicinal difluoro gauche conformation being more stable than the corresponding anti conformation [7][8][9]. O'Hagan has demonstrated that vicinal difluoride substitution along a hydrocarbon chain of a fatty acid leads to conformational rigidity or disorder depending on the relative stereochemistry of the fluorine atoms, which originates from the enforcing or opposing fluorine gauche and hydrocarbon anti low-energy conformations [10]. As an extension, multi-vicinal tri-to hexafluorinated chains have been synthesised [11][12][13][14][15][16], which revealed yet another effect on the conformational behaviour, i.e. that conformations containing parallel 1,3-C-F bonds are destabilised. As an application, liquid crystals have been prepared containing a vicinal difluoride motif [14,17,18].
Efficient stereodefined synthesis of vicinal difluoride moieties is not straightforward. Direct methods include fluorination of alkenes with F 2 [19], XeF 2 [20], or hypervalent iodine species [21]. Such approaches often display poor stereoselectivity or result in rearrangement products. Treatment of 1,2-diols with SF 4 [22,23], DAST [24], or deoxofluor [25] also leads to vicinal difluorides. Reaction with vicinal triflates has also been successful in some cases [7,26]. A common two-step method involves opening of an epoxide to give the corresponding fluorohydrin [27], followed by the conversion of the alcohol moiety to the fluoride [28]. Another two-step method is halofluorination of alkenes and subsequent halide substitution with silver fluoride [9,29,30].
The introduction of multiple fluorine atoms is often a cumbersome process, and in many cases a fluorinated building block approach [31,32] is more efficient. Known vicinal difluoride containing building blocks include (racemic) C 2 -symmetric and meso-2,3-difluorosuccinic acids (or esters) 1,2 ( Figure 1) [9,22,23,33,34]. Herein we describe the first synthesis of meso-2,3-difluoro-1,4butanediol 3 as a further simple vicinal difluoride building block as well as its successful monosilylation, and our attempts to employ 3 for the synthesis of fluorinated hydrocarbons.

Synthesis
The synthesis of 3 was achieved from meso-epoxide 4, which was obtained from (Z)-2-butene-1,4-diol in excellent yield according to the published two-step sequence [35]. The optimisation of the reaction of 4 with fluoride sources is shown in Table 1.
Reaction with Olah's reagent [29] proceeded in excellent yield ( Table 1, entry 1), however, the product was isolated as a mixture of isomers, which were not further characterised. Reaction with potassium hydrogen difluoride in ethylene glycol [36,37] gave the fluorohydrin in only modest yield (entry 2). Interestingly, the product arising from epoxide ring opening by ethylene glycol, 6, was isolated in 50% yield. The addition of molecular sieves (entry 3) led to complete conversion to 6 (TLC analysis). No reaction took place when DMSO (entry 4) or DMF/18-crown-6 were used as solvents [38,39] (entry 5). With Bu 4 NH 2 F 3 as the fluoride source [40,41], 11% of the desired product (together with some elimination byproducts) was obtained when xylene was used as solvent (entry 6). However, reaction with a mixture of Bu 4 NH 2 F 3 and KHF 2 in the absence of solvent [42][43][44] led to an excellent 91% yield of the desired product 5 albeit after a relatively long reaction time (entry 8).
The subsequent conversion to 3 is shown in Scheme 1. Treatment of 5 with DAST in DCM at reflux temperature only gave 7 in 29% yield (not shown). A slight improvement (40% yield) was obtained when the reaction was conducted in hexane or toluene, but a procedure in which DAST was added to a solution of 5 in toluene at room temperature, followed by the add- ition of pyridine [28] and heating the reaction mixture for a prolonged period gave the desired vicinal difluoride in good yield. Nevertheless, while this procedure was deemed sufficiently safe to conduct at about the 50 mmol scale, further upscaling with a more thermally stable fluorinating reagent such as deoxofluor [45], Fluolead [46], or aminodifluorosulfinium tetrafluoroborate [47] would be recommended. Subsequent alcohol deprotection gave the target compound in almost quantitative yield in multigram quantities.
The potential of 3 as a building block, in particular for the construction of longer aliphatic chains of varying length, was investigated next. Thus (Scheme 2), the diol moiety in 3 was monoprotected as a silyl ether, and the remaining alcohol group was activated as the corresponding tosylate 9, triflate 10, mesylate 11, and bromide 12 as precursors for chain extension. Nucleophilic substitution of similar tosylates with phenolate nucleophiles has been previously described [18]. Reaction of 9-12 with a number of carbon nucleophiles was investigated.
Unfortunately, reaction of 9-12 with alkyl Grignard and acetylide reagents did not lead to the desired chain extension. Reaction of 9 or 10 with a sodium or lithium acetylide led to decomposition, while 12 did not react under these conditions. Treatment of 11 with C 9 H 19 MgBr/CuBr was unsuccessful, whilst surprisingly, when 12 was subjected to this reagent combination (Scheme 3), the defluorinated reaction products 13 and 14 were obtained. We have not yet deduced an acceptable explanation for this unexpected result.
Scheme 3: Reaction of 12 leading to defluorinated products.

Crystallographic analysis
Compounds 7 and 3 yielded colourless crystals suitable for study by single crystal X-ray diffraction [48]. The dibenzyl ether 7 crystallises in the monoclinic P2 1 /c space group with half a molecule of 7 in the asymmetric unit. The molecule possesses crystallographic inversion symmetry. Two conformers are present in the crystal (55:45) which differ only in the sign of the torsion angle of the rings ( Figure 2). The disparity in the amounts of each conformer present gives rise to the disorder observed in the crystal structure. The vicinal difluoro group adopts an anti conformation with the F-C-C-F dihedral angle exactly 180°, which manifests itself in the crystallographic inversion centre. Nevertheless, each benzyloxy group does adopt a gauche conformation with its adjacent fluoro substituent where the F-C-C-O dihedral angle is 71.5°. Although strong H-bonding interactions are absent within the crystal, each molecule displays eight short contacts less than the sum of the van der Waals radii to its four nearest neighbours; three C-F···H-C contacts (2.554 Å, 2.581 Å and 2.637 Å) for each fluorine, and a pair of C-H···π contacts (2.662 Å to centroid of ring). The hydrogen atoms involved in the C-F contacts are an aromatic proton, the CHF and a CHHOBn proton ( Figure 3). The diol 3 crystallises in the tetragonal space group I4 1 /a with half a molecule of 3 in the asymmetric unit. This molecule also displays crystallographic inversion symmetry. In common with 7, the vicinal difluoro group of 3 adopts an anti conformation with a symmetry-constrained dihedral angle of 180°, and the hydroxyl groups adopt gauche conformations with the adjacent fluoro atoms with F-C-C-O dihedral angles of 66.8°( Figure 4).    [9]. Of these, only difluorosuccinic acid crystallises with the vicinal difluoro group in the expected gauche conformation, whilst both other structures, in common with the structures described in this work, contain the vicinal difluoro group in an anti conformation. The conformation of vicinal difluorides in solution can also be deduced from NMR studies. Schlosser has reported that the 3 J H-F is around 22 Hz when the fluorines are in the syn configuration, because of a preferred gauche conformation, and around 14 Hz when in the anti configuration, because there is no overall preferred conformation [28]. Unfortunately, we were unable to extract 3 J H-F values from the second order signals in both the 1

Conclusion
The synthesis of meso-2,3-difluoro-1,4-butanediol 3 was achieved in 5 steps from (Z)-1,4-butenediol in 40% overall yield on a multigram scale. A high-yielding (94%) monosilylation was also achieved, but all attempts for chain extension met with failure. Crystallographic analysis revealed that the vicinal fluorine atoms in 3 and its dibenzyl ether 7 are in the anti conformation. Reaction solvents were dried before use as follows: THF and Et 2 O were distilled from sodium/benzophenone; CH 2 Cl 2 and Et 3 N were distilled from CaH 2 ; toluene was distilled from sodium.

Experimental
X-ray data crystal structure analyses: Suitable crystals were selected and data collected on a Bruker Nonius Kappa CCD Area Detector equipped with a Bruker Nonius FR591 rotating anode (λ(MoKα) = 0.71073 Å) at 120 K driven by COLLECT [50] and processed by DENZO [51] software and corrected for absorption by using SADABS [52]. The structures were determined in SHELXS-97 and refined using SHELXL-97 [53]. All non-hydrogen atoms were refined anisotropically with hydrogen atoms included in idealised positions with thermal parameters riding on those of the parent atom.

meso-1,4-Bis(benzyloxy)-2,3-difluorobutane (7)
DAST (9.6 mL, 72.7 mmol) was added to a solution of fluorohydrin 5 (17.0 g, 55.9 mmol) in toluene (75 mL) and the mixture stirred at r.t. for 5 min. Pyridine (11.9 mL, 145 mmol) was then added and the solution stirred at 70 °C for a further 16 h. The reaction mixture was cooled, poured into sat. NaHCO 3 (100 mL) and Et 2 O (100 mL). The organic layer was washed successively with sat. NaHCO 3 (100 mL) and brine (100 mL), dried over MgSO 4 , filtered and concentrated in vacuo. The crude product was quickly purified by column chromatography (EtOAc/petroleum ether 0% to 5%) to afford a mixture which was recrystallised from hot petroleum ether. The filtrate was concentrated and recrystallised again from hot petroleum ether. The recrystallisation process was carried out for a third time to afford difluoride 7 as a white crystalline solid (overall yield 10.1 g, 59%

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